Piperazine derivatives

Abstract

This invention relates to piperazine derivatives of the formula: wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or preventing Tachykinin-mediated diseases in human being or animals.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
       wherein  
       Y is bond or lower alkylene,  
       R 1  is aryl which is substituted with 1 to 3 same or different substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl, nitro, amino, lower alkylamino, di(lower)alkylamino, lower alkylthio, lower alkylsulfonyl, cyclo(lower)alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl, di(lower)alkylaminosulfonyl, pyrrolidinylsulfonyl, morpholinylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, pyrrolyl and pyridyl;  
       R 2  is aryl which is substituted with 1 to 3 same or different substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl, mono(or di or tri)halo(lower)alkylsulfonyloxy, halogen, lower alkylenedioxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxy(lower)alkoxy(lower)alkoxy, hydroxy, diphenyl(lower)alkylsilyloxy, tri(lower)alkylsilyloxy, hydroxy(lower)alkyl, cyano, amino, [mono(or di or tri)halo(lower)alkylcarbonyl]amino, lower alkylamino, N-(lower alkyl)-[mono(or di or tri)halo(lower)alkylcarbonyl]amino, pyrrolidinyl and morpholinyl which may be substituted with lower alkoxy(lower)alkyl or lower alkyl;  
       R 3  is hydrogen or lower alkyl; and  
       R 4  is (3-pyridyl)methyl; 
 (3-pyridyl)ethyl;  
 3-(3-pyridyl)propyl;  
 3-(3-pyridyl)propenyl;  
 3-(3-pyridyl)propynyl;  
 thiazolyl(lower)alkyl, 1,2,4-thiadiazolyl(lower)alkyl or 1,2,4-oxadiazolyl(lower)alkyl, each of which is substituted with halogen, amino, lower alkylamino or di(lower)alkylamino;  
 pyrazolylmethyl which may be substituted with triphenyl(lower)alkyl or hydroxy(lower)alkyl;  
 pyrazolyl(lower)alkyl which is substituted with lower alkyl, lower alkoxy(lower)alkylmorpholinyl(lower)alkyl or lower alkoxy(lower)alkylmorpholinylcarbonyl-(lower)alkyl;  
 pyrrolidinyl(lower)alkyl which is substituted with 1 or 2 same or different substituent(s) selected from the group consisiting of hydroxy, hydroxy(lower)alkyl, lower alkoxy and lower alkoxy(lower)alkyl;  
 piperidylmethyl;  
 piperidyl(lower)alkyl which is substituted with 1 or 2 same or different substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy(lower)alkyl;  
 [2,6-di[hydroxy(lower)alkyl]piperidyl](lower)alkyl;  
 (2,6-dimethylmorpholino)(lower)alkyl;  
 (2,2-dimethylmorpholino)(lower)alkyl;  
 (3,3-dimethylmorpholino)(lower)alkyl;  
 (cis-3,5-dimethylmorpholino)(lower)alkyl;  
 ((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl;  
 ((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl;  
 (2-methoxymethylmorpholino)(lower)alkyl;  
 (3-methoxymethylmorpholino)(lower)alkyl;  
 (2-methoxymethyl-5-methylmorpholino)(lower)alkyl;  
 (2-methoxymethyl-5,5-dimethylmorpholino)(lower)-alkyl;  
 (3,5-dimethoxymethylmorpholino)(lower)alkyl;  
 (2,2-dimethoxymethylmorpholino)(lower)alkyl;  
 (2,3-dimethoxymethylmorpholino)(lower)alkyl;  
 (2,6-dimethoxymethylmorpholino)(lower)alkyl;  
 (2-methoxymethylmorpholino)(lower)alkenyl;  
 (3,3-dimethylmorpholino)(lower)alkynyl;  
 (2-methoxymethylmorpholino)(lower)alkynyl;  
 (2-methoxymethyl-5-methylmorpholino)(lower)alkynyl;  
 quinoly(lower)alkyl;  
 [1H-pyrrolo[3,2-b]pyridinyl](lower)alkyl;  
 [4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl](lower)-alkyl;  
 [3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazinyl](lower)-alkyl;  
 (5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl)(lower)-alkyl; or  
 lower alkyl which is substituted with a saturated heterocyclic group of the formula:  
                     
  (wherein r, s and t are each integer of 1 to 2, and q is integer of 0 to 2) which may be substituted with one or two lower alkyl, provided that when  
 
       R 4  is 3-(3-pyridyl)propyl; 
 3-(3-pyridyl)propenyl;  
 pyrazolylmethyl which may be substituted with hydroxy(lower)alkyl;  
 (2-methoxymethylmorpholino)(lower)alkyl;  
 (3-methoxymethylmorpholino)(lower)alkyl; or  
 (2-methoxymethylmorpholino)(lower)alkynyl, then  
 
       R 2  is not di(lower)alkylphenyl, and a salt thereof.  
     
   
   
       2 . The compound of  claim 1 , in which 
 Y is lower alkylene;    R 1  is phenyl which is substituted with 1 or 2 same or different substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, mono(or di or tri)halo(lower)alkyl, nitro, amino, lower alkylamino, di(lower)alkylamino, lower alkylthio, lower alkylsulfonyl, cyclo(lower)alkylsulfonyl, aminosulfonyl, lower alkylaminosulfonyl, di(lower)alkylaminosulfonyl, pyrrolidinylsulfonyl, morpholinylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, pyrrolyl and pyridyl;    R 2  is phenyl which is substituted with 1 or 2 same or different substituent(s) selected from the group consisting of lower alkyl, mono(or di or tri)halo(lower)alkyl, mono(or di or tri)halo(lower)alkylsulfonyloxy, halogen, lower alkylenedioxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxy(lower)alkoxy(lower)alkoxy, hydroxy, diphenyl(lower)alkylsilyloxy, tri(lower)alkylsilyloxy, hydroxy(lower)alkyl, cyano, amino, [mono(or di or tri)halo(lower)alkylcarbonyl]amino, lower alkylamino, N-(lower alkyl)-[mono(or di or tri)halo(lower)alkylcarbonyl]amino, pyrrolidinyl and morpholinyl which may be substituted with lower alkoxy(lower)alkyl or lower alkyl;    R 3  is hydrogen; and    R 4  is 3-(3-pyridyl)propyl; 
 3-(3-pyridyl)propynyl;  
 (2,6-dimethylmorpholino)(lower)alkyl;  
 (3,3-dimethylmorpholino)(lower)alkyl;  
 (cis-3,5-dimethylmorpholino)(lower)alkyl;  
 ((3S,5S)-3,5-dimethylmorpholino)(lower)alkyl;  
 ((3S,5R)-3,5-dimethylmorpholino)(lower)alkyl;  
 (2-methoxymethylmorpholino)(lower)alkyl;  
 (3-methoxymethylmorpholino)(lower)alkyl;  
 (2-methoxymethyl-5-methylmorpholino)(lower)alkyl;  
 (2-methoxymethyl-5,5-dimethylmorpholino)(lower)-alkyl;  
 (3,5-dimethoxymethylmorpholino)(lower)alkyl;  
 (2,3-dimethoxymethylmorpholino)(lower)alkyl; or  
 (2-methoxymethylmorpholino)(lower)alkenyl, provided that when  
   R 4  is 3-(3-pyridyl)propyl; 
 (2-methoxymethylmorpholino)(lower)alkyl; or  
 (3-methoxymethylmorpholino)(lower)alkyl, then  
   R 2  is not di(lower)alkylphenyl.    
   
   
       3 . The compound of  claim 2 , in which 
 Y is C 1 -C 4  alkylene;    R 1  is bis[mono(or di or tri)halo(C 1 -C 4 )alkyl]phenyl;    R 2  is phenyl which is substituted with 1 or 2 same or different substituent(s) selected from the group consisting of C 1 -C 4  alkyl, mono(or di or tri)halo(C 1 -C 4 )alkyl, halogen, C 1 -C 4  alkoxy and hydroxy;    R 3  is hydrogen; and    R 4  is 3-(3-pyridyl)propyl; 
 3-(3-pyridyl)propynyl;  
 (2,6-dimethylmorpholino)(C 1 -C 4 )alkyl;  
 (2-methoxymethylmorpholino)(C 1 -C 4 )alkyl;  
 (3-methoxymethylmorpholino)(C 1 -C 4 )alkyl; or  
 (2-methoxymethyl-5-methylmorpholino)(C 1 -C 4 )alkyl, provided that when  
   R 4  is 3-(3-pyridyl)propyl; 
 (2-methoxymethylmorpholino)(C 1 -C 4 )alkyl; or  
 (3-methoxymethylmorpholino)(C 1 -C 4 )alkyl, then  
   R 2  is not di(C 1 -C 4 )alkylphenyl.    
   
   
       4 . A compound of  claim 3 , which is selected from the group consisting of 
 (1) 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-[(3R)-3-(methoxymethyl)morpholino]-ethyl]piperazine,    (2) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-(cis-2,6-dimethylmorpholino)ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine,    (3) 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[2-[(2S,5S)-2-methoxymethyl-5-methylmorpholino]ethyl]piperazine,    (4) 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3-pyridyl)-2-propynyl]piperazine,    (5) 1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine,    (6) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]-2-(3-hydroxy-4-methylbenzyl)piperazine,    (7) 1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-4-[3-(3-pyridyl)propyl]piperazine,    (8) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-chloro-3-hydroxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine,    (9) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-(4-fluoro-3-methoxybenzyl)-4-[2-[(2S)-2-(methoxymethyl)morpholino]-ethyl]piperazine, and    (10) (2R)-1-[3,5-Bis(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine,    or a pharmaceutically acceptable salt thereof.    
   
   
       5 . A process for the preparation of the compound of  claim 1  or a salt thereof, which comprises, 
 (1) reacting a compound of the formula (II):                           wherein R 1 , R 2 , R 3  and Y are each as defined in  claim 1 , or a salt thereof, with a compound of the formula (III):     W 1 —R 4   (III) wherein R 4  is as defined in  claim 1  and W 1  is a leaving group,    or a salt thereof to give a compound of the formula (I):                          wherein R 1 , R 2 , R 3 , R 4  and Y are each as defined in  claim 1 , or a salt thereof, or      (2) subjecting a compound of the formula (Ia):                          wherein R 1 , R 2 , R 3  and Y are each as defined above, 
 R 5  is 3-pyridyl, and  
 Z 1  is lower alkynylene,  
   or a salt thereof to a reduction reaction to give a compound of the formula (Ib):                          wherein R 1 , R 2 , R 3 , Y and R 5  are each as defined above, and 
 X 1  is lower alkylene,  
   or a salt thereof.    
   
   
       6 . A pharmaceutical composition which comprises, as an active ingredient, a compound of  claim 1  or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.  
   
   
       7 . A compound of  claim 1  for use as a medicament.  
   
   
       8 . A method for treating or preventing Tachykinin-mediated diseases which comprises administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof to human being or animals.  
   
   
       9 . A compound of  claim 1  for use as Tachykinin antagonist.  
   
   
       10 . Use of a compound of  claim 1  for manufacture of a medicament for treating or preventing Tachykinin-mediated diseases.